WO2014203177A1 - (r)-3-[1-(2,6-dichloro-3-fluorophényl)méthoxy]-5-[1-(pipéridin-4-yl)-1h-pyrazol-4-yl]pyridine-2-amine amorphe - Google Patents

(r)-3-[1-(2,6-dichloro-3-fluorophényl)méthoxy]-5-[1-(pipéridin-4-yl)-1h-pyrazol-4-yl]pyridine-2-amine amorphe Download PDF

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Publication number
WO2014203177A1
WO2014203177A1 PCT/IB2014/062361 IB2014062361W WO2014203177A1 WO 2014203177 A1 WO2014203177 A1 WO 2014203177A1 IB 2014062361 W IB2014062361 W IB 2014062361W WO 2014203177 A1 WO2014203177 A1 WO 2014203177A1
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Prior art keywords
dichloro
piperidin
pyrazol
amine
ethoxy
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PCT/IB2014/062361
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English (en)
Inventor
Lavkumar UPALLA
Rampalli SRIRAM
Chantibabu PATNEEDI
Chandrasekhar DANGUDUBIYYAM
Akshaykant CHATURVEDI
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Shilpa Medicare Limited
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Publication of WO2014203177A1 publication Critical patent/WO2014203177A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to a process for preparation of amorphous (R)-3-[l -(2,6- Dichloro-3-fluorophenyl) ]pyridin-2-amine (I).
  • the present invention also relates to the process for the preparation of amorphous premix of (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l -(piperidin-4-yl)- lH-pyrazol-4- yl]pyridin-2-amine premix.
  • the invention further relates to pharmaceutical compositions comprising amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l -(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin- 2-amine or its premix, having anti-cancer activity.
  • Crizotinib is a kinase inhibitor indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive. It was approved by USFDA in August of 2011 and is marketed under the trade name XALKORITM. Crizotinib is also undergoing clinical trials testing its safety and efficacy in anaplastic large cell lymphoma, neuroblastoma, and other advanced solid tumors in both adults and children. Crizotinib is chemically mentioned in the USFDA label as (R)-3-[l-(2,6-Dichloro-3- fluorophenyl)ethoxy]-5-[l -amine (I).
  • Crizotinib structure contains one chiral center. It is a non-hygroscopic, white to pale yellow powder which is insoluble in water, though being highly soluble in acidic pH. Crizotinib is defined in class IV (low solubility and low permeability) under the Biopharmaceutics Classification System (BCS).
  • BCS Biopharmaceutics Classification System
  • Cui, et al. in US 7,230,098 B2 provided the first generic disclosure of (R)-3-[l -(2,6- Dichloro-3-fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine (also known as Crizotinib). Further Cui, et al. in US 7,858,643 B2 provided the specific disclosure of Crizotinib and its pharmaceutically acceptable salts. This patent also describes the process for preparation of Crizotinib.
  • Example 19 of U.S. patent application Ser. No. 11/212,331 i.e. US 7,858,643 B2 describes the preparation of Crizotinib (Compound I) which was found to be amorphous. However actually this disclosure appears to relate with compound other than Crizotinib. It is also disclosed in this patent that new polymorphic forms of Crizotinib base were required so as to have improved crystallinity, dissolution properties, and/or decreased hygroscopicity, while maintaining chemical and enantiomeric stability properties.
  • Example 19 of US 7,858,643 B2 example 19 compound is 3-[(R)-l-(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-5-(l-piperidin-4- yl- lH-pyrazol-4-yl)-pyridin-2-ylamine acetate, which is not Crizotinib.
  • Even the analytical data provided for this compound of Example 19 shows- a. LCMS mass value of 434 [M+], which is indicative of absence of Crizotinib; and b. l H NMR results with three extra protons at ⁇ 5—1.80 ppm because of presence of acetate salt, indicating absence of Crizotinib which is a free base compound.
  • Amorphous (R)-3-[l-(2,6-Dichloro-3- fluorophenyl) ethoxy] -5-[l - (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine obtained by the process of the present invention is non-hygroscopic, chemically and enantiomerically stable and has good dissolution properties.
  • the present invention provides an amorphous (R)-3-[l-(2,6-Dichloro- 3-fluorophenyl)ethoxy]-5-[l -(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine.
  • the present invention also relates to a process for preparation of amorphous premix of (R)-3-[l-(2, 6-Dichloro-3 -fluorophenyl) ethoxy]-5-[l -(piperidin-4-yl)- lH-pyrazol-4-yl] pyridin-2-amine (I)
  • the present invention also relates to a composition
  • a composition comprising amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l -(piperidin-4-yl)- lH-pyrazol-4- yl]pyridin-2-amine, of which at least 95% by total weight of (R)-3-[l-(2,6-Dichloro-3-fluoro phenyl)ethoxy]-5-[l -(piperidin-4-yl)- lH-pyrazol-4-yl]pyridin-2-amine in the composition, is the amorphous form.
  • composition is substantially free of any other known forms of (R)-3- [ 1 -(2,6 -Dichloro-3 -fluorophenyl)ethoxy] -5 - [ 1 -(piperidin-4-yl)- 1 H-pyrazol-4-yl]pyridin-2- amine.
  • the present application also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l -(piperidin-4-yl)- lH-pyrazol-4-yl]pyridin-2-amine or its premix of the present application and at least one or more pharmaceutically acceptable excipients.
  • Fig. 1 is an example of X-ray powder diffraction ("XRPD") pattern of (R)-3-[l -(2,6- Dichloro-3-fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine amorphous form.
  • XRPD X-ray powder diffraction
  • Fig. 2 is an example of FT-IR spectrum of (R)-3-[l -(2,6-Dichloro-3-fiuorophenyl)ethoxy]- 5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine amorphous form.
  • Fig. 3 is an example of l H NMR spectrum of (R)-3-[l-(2,6-Dichloro-3- fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine amorphous form.
  • Fig. 4 is an example of mass spectrum of (R)-3-[l -(2,6-Dichloro-3-fiuorophenyl)ethoxy]- 5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine amorphous form.
  • Fig. 5 is an example of TGA thermogram of (R)-3-[l-(2,6-Dichloro-3-fluorophenyl) emoxy]-5-[l -(piperidin-4-yl)- lH-pyrazol-4-yl]pyridin-2-amine amorphous form.
  • Fig. 6 is an example of X-ray powder diffraction ("XRPD") pattern of (R)-3-[l -(2,6- Dichloro-3-fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine premix amorphous form as obtained according to example 3.
  • XRPD X-ray powder diffraction
  • embodiments of the present invention relate to the amorphous (R)- 3-[l-(2,6-Dichloro-3-fiuorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -IH- pyrazol-4-yl] pyridine -2-amine and process for preparation thereof.
  • Step a) comprises providing a solution of (R)-3-[l -(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l - (piperidin-4-yl)- lH-pyrazol-4-yl]pyridin-2-amine in an organic solvent;
  • Crizotinib base Crizotinib base (R)-3-[l-(2, 6-Dichloro-3 -fluorophenyl) ethoxy]-5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl] pyridin-2-amine (or Crizotinib base) is provided as a solution in an organic solvent wherein organic solvent may be selected from a water miscible organic solvent comprising of C 1 -C 4 alcohol, THF, acetone, MTBE, DMF, DMSO, DMAc, NMP or a mixture thereof.
  • C 1 -C 4 alcohol may further be selected from methanol, ethanol, wo-propanol, «-butanol or tert- butanol.
  • the reaction solution is prepared at an ambient temperature of 25-30 °C.
  • amount of organic solvent used to prepare the reaction solution may range from 2 to 25 times w/v (g/mL) as compared to the weight of Crizotinib used as the starting material.
  • Step b) comprises heating the reaction mixture to a temperature ranging between 40 °C and the boiling point of the organic solvent used;
  • Reaction mixture prepared in step a) is heated to a temperature ranging between 40 °C and the boiling point of the organic solvent used, along with continuous stirring to provide a clear solution.
  • temperature employed for the current step was 50-55 °C.
  • the reaction mixture is maintained at the same raised temperature for a time duration of 20 mins to 1 hr.
  • Step c) comprises cooling the reaction mixture to a temperature of 30°C or below;
  • reaction mixture obtained in step b) is slowly cooled to a temperature of 30°C or below. In one of the specific embodiment reaction mixture temperature is lowered to 25 °C.
  • Step d) comprises adding a co-solvent to the reaction mixture
  • co-solvent is added at the same temperature.
  • Co-solvent may be selected from water, C 1 -C 4 alcohol, THF, acetone, MTBE, DMF, DMSO, DMAc, hexane, NMP or a mixture thereof, with the proviso that organic solvent used in step a) and the co-solvent used in this step are not the same.
  • Amount of co-solvet used may range from 15 to 50 times (v/w: mL/g) w.r.t. the amount of Crizotinib used as starting material.
  • Addition of the co-solvent to the reaction mixture shall be performed slowly over a time duration ranging from 10 mins to 1 hour. In one of the preferred embodiments the addition of 3.0 mL co-solvent water to the reaction mixture was done drop- wise over a time duration of 10 mins. With the addition of co-solvent turbidity starts to appear in the reaction mixture.
  • Step e) comprises isolating the amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5- [ 1 -(piperidin-4-yl)- lH-pyrazol-4-yl]pyridin-2-amine.
  • the solvents are recovered up to 40 to 85% of the original reaction mass.
  • Recovery of the solvent may be performed under reduced pressure conditions by techniques known to the person skilled in the art. In one of the preferred embodiment recovery of the solvent may be performed by distillation under vacuum at a raised temperature of 35-55 °C.
  • reaction mass obtained is then cooled to a temperature below 20 °C. In one of the preferred embodiment cooling of the reaction mass is performed till 10-15 °C. The cooled reaction mass is subjected to stirring for time duration of
  • the reaction mass may optionally be filtered by employing any of the conventional process for filtration.
  • filtration was performed by using micron filter paper.
  • the solid mass obtained is given washing with a suitable solvent like chilled DM water etc. and then subjected to drying till a constant weight is acheived. Drying may be performed at a raised temperature of 45-75 °C, depending upon the choice of solvents initially used in the process.
  • Drying may be also be performed by any conventional process not limited to spray drying or distillation to remove the solvent. Drying may be performed under reduced pressure conditions also. Reduced pressure conditions may be suitably utilized by person skilled in the art in order to obtain the dried material. The drying may be performed for time ranging from 2 to 20 hrs depending upon the physical attributes of the end product obtained i.e. amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-
  • Process of isolating amorphous (R)-3-[l -(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l - (piperidin-4-yl)- lH-pyrazol-4-yl]pyridin-2-amine may further comprise processes but not limited to conventional processes including scrapping and if required filtering from slurry which may be carried out at room temperature for the suitable durations to retain the amorphous form characteristics.
  • the process related impurities that appear in the impurity profile of the (R)-3-[l-(2,6- Dichloro-3-fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH ⁇ yrazol-4-yl]pyridin-2-amine may be substantially removed by the process of the present invention resulting in the formation of amorphous material of high purity.
  • the merit of the process according to the present invention resides in that - product isolated after drying is directly obtained as amorphous (R)-3-[l-(2,6-Dichloro-3- fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH ⁇ yrazol-4-yl]pyridin-2-amine. Said material is found devoid of any crystal lattice and is adequately stable to handle and store for longer time (alteast up to more than 6 months) without any significant or measurable change in its morphology and physicochemical characteristics.
  • Amorphous (R)-3-[l-(2,6-Dichloro-3- fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH ⁇ yrazol-4-yl]pyridin-2-amine obtained according to the process of the present invention results in the final API purity by HPLC of more than 99 % w/w.
  • Amorphous (R)-3-[l -(2, 6-Dichloro-3-fiuorophenyl) ethoxy]-5-[l-(piperidin-4-yl)-lH- pyrazol-4-yl] pyridin-2-amine obtained by the process of the present invention has XRPD pattern similar to Fig- 1 (indicating a solid form that lacks the long-range order-a characteristic of crystals, and having no pattern or structure), FTIR spectrum similar to Fig-2, l H NMR spectrum similar to Fig-3, Mass spectrum similar to Fig-4 and TGA thermograph similar to Fig-5.
  • end product obtained by following the complete process of the present invention is substantially amorphous which has at least more than 90% amorphous nature.
  • Amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine obtained by the process of the present invention is found to be non-hygroscopic, chemically and enantiomerically stable and posseses good dissolution properties.
  • amorphous Crizotinib of this invention may be a solvated or a non-solvated form. In a preferred embodiment, it has been observed by the inventors of the present application that the amorphous Crizotinib obtained by the present process is non-solvated and remains so on storage with loss on drying as measured by TGA up to not more than 2%.
  • amorphous (R)-3-[l-(2,6-Dichloro-3 -fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) - 1H- pyrazol-4-yl] pyridine -2- amine described herein may be characterized by X-ray powder diffraction pattern (XRPD).
  • the invention also relates to a composition containing amorphous (R)-3-[l -(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l - (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine, of which at least 95 % by total weight of (R)-3-[l-(2,6-Dichloro-3-fiuorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine in the composition, is the amorphous form.
  • the composition may be substantially free of any other known forms of (R)-3-[l- (2,6-Dichloro-3-fiuorophenyl) ethoxy] -5-[l - (piperidin-4-yl) - 1H- pyrazol-4-yl] pyridine -2- amine.
  • the amorphous (R)-3-[l-(2,6-Dichloro-3 -fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) - 1H- pyrazol-4-yl] pyridine -2- amine obtained by the process of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules.
  • the active product is mixed with one or more pharmaceutically acceptable excipients.
  • the drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin.
  • premix comprising one or more pharmaceutically acceptable excipients in the range of 1 to 50% w/w with amorphous (R)-3-[l-(2,6-Dichloro-3-fiuorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine, while retaining the amorphous nature of the premix.
  • Amorphous premix may be prepared by conventional process of dissolving in the organic solvent along with requisite amount of pharmaceutically acceptable excipients required in premix composition.
  • compositions include but are not limited to polymers like HPMC, MCC or PVP.
  • the solvent is removed by conventional processes like use of rotavapor or spray drying - to achieve the amorphous premix solid dispersion.
  • the present invention also includes a process for the preparation amorphous premix of (R)-3-[l-(2, 6-Dichloro-3 -fluorophenyl) ethoxy]-5-[l-(piperidin-4-yl)- lH-pyrazol-4-yl] pyridin-2-amine (I)
  • the amorphous premix of (R)-3-[l-(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine remains well dispersed in the solid form, of which at least 95% by total weight of (R)-3-[l-(2,6-Dichloro-3-fiuoro phenyl)ethoxy]-5-[l- (piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine is the amorphous form.
  • amorphous solid dispersion comprising of polyvinylpyrrolidone and (R)-3-[l-(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l- (piperidin-4- yl) -1H- pyrazol-4-yl] pyridine -2- amine (in weight ratio of 50:50) was found to be completely amorphous in nature with no crystalline peaks observed during their conventional stability studies-while packed and shelved under suitable conditions.
  • compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions.
  • a solvent or vehicle propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed.
  • These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents.
  • the sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
  • compositions comprising amorphous (R)-3-[l-(2,6-Dichloro-3-fiuorophenyl) ethoxy] -5-[l - (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine according to the present application include, but are not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-ge latinized starch and the like; dis integrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate,
  • compositions / dosage forms of amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine and its premix according to the present application may also comprise to include the pharmaceutically acceptable carriers used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.
  • Example-01 Process for preparation of amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine
  • the solvent mixture from the reaction was recovered upto about 75% v/v of the total volume by distillation under vacuum at a temperature of 35 °C,.
  • the reaction mass was cooled to 25-30 °C and then further cooled to 15°C, where it was stirred for 2 h.
  • the isolated product was filtered and washed with 0.6 mL chilled DM water.
  • Example-02 Process for preparation of amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine
  • Example-03 Process for preparation of amorphous premix of (R)-3-[l-(2,6-Dichloro-3- fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine (Using Povidone)
  • Example-04 Process for preparation of amorphous premix of (R)-3-[l-(2,6-Dichloro-3- fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine (Using Povidone and microcrystalline cellulose)

Abstract

L'invention concerne un procédé de préparation de (R)-3-[1-(2,6- dichloro-3-fluorophényl)éthoxy]-5-[1-(pipéridine-4-yl)-1H-pyrazol-4-yl]pyridine-2-amine amorphe (I) ou son prémélange. (I) L'invention concerne aussi (R)-3-[1-(2,6-dichloro-3-fluorophényl)éthoxy]-5-[1-(pipéridine-4-yl)-1H-pyrazol-4-yl]pyridine-2-amine amorphe (I) présentant un pic de spectre de masse à environ [M+] = 450,1, au moins trois pics IR choisis parmi 3 470 cm -, 3 388 cm -, 1 117 cm -, 1 252 cm -, ou 740 cm - ± 2,0 cm - et moins de 2 % p/p de composés volatils mesurés jusqu'à 170 °C par TGA. L'invention concerne également des compositions pharmaceutiques comprenant (R)-3-[1-(2,6-dichloro-3-fluorophényl)éthoxy]-5-[1-(pipéridine-4-yl)-1H-pyrazol-4-yl]pyridine-2-amine amorphe (I) ou son prémélange, présentant une activité antinéoplasique.
PCT/IB2014/062361 2013-06-18 2014-06-18 (r)-3-[1-(2,6-dichloro-3-fluorophényl)méthoxy]-5-[1-(pipéridin-4-yl)-1h-pyrazol-4-yl]pyridine-2-amine amorphe WO2014203177A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104730028A (zh) * 2015-03-12 2015-06-24 浙江华峰氨纶股份有限公司 用于氨纶丝中溶剂残存含量的近红外光谱检测方法
CN105294657A (zh) * 2015-10-30 2016-02-03 西华大学 一种克里唑替尼的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006021881A2 (fr) * 2004-08-26 2006-03-02 Pfizer Inc. Composes aminoheteroaryle a substitution pyrazole servant d'inhibiteurs de proteine kinase
WO2006021884A2 (fr) * 2004-08-26 2006-03-02 Pfizer Inc. Composes d'aminoheteroaryle enantiomeriquement purs utilises comme inhibiteurs de proteine kinase
EP2620140A1 (fr) * 2012-01-26 2013-07-31 ratiopharm GmbH Compositions contenant crizotinibe
WO2013181251A1 (fr) * 2012-05-29 2013-12-05 Ratiopharm Gmbh Sel de chlorhydrate de crizotinib sous forme cristalline

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006021881A2 (fr) * 2004-08-26 2006-03-02 Pfizer Inc. Composes aminoheteroaryle a substitution pyrazole servant d'inhibiteurs de proteine kinase
WO2006021884A2 (fr) * 2004-08-26 2006-03-02 Pfizer Inc. Composes d'aminoheteroaryle enantiomeriquement purs utilises comme inhibiteurs de proteine kinase
EP2620140A1 (fr) * 2012-01-26 2013-07-31 ratiopharm GmbH Compositions contenant crizotinibe
WO2013181251A1 (fr) * 2012-05-29 2013-12-05 Ratiopharm Gmbh Sel de chlorhydrate de crizotinib sous forme cristalline

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104730028A (zh) * 2015-03-12 2015-06-24 浙江华峰氨纶股份有限公司 用于氨纶丝中溶剂残存含量的近红外光谱检测方法
CN105294657A (zh) * 2015-10-30 2016-02-03 西华大学 一种克里唑替尼的制备方法

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